Syphilis is a chronic bacterial infection that follows a predictable early clinical course: development of a local chancre that resolves spontaneously; subsequent appearance of the secondary disseminated skin rash that also resolves without antibiotic therapy; and a prolonged asymptomatic stage (latency) that usually continues for the lifetime of the individual. Untreated, this infection may cause fetal and neonatal morbidity and mortality through infection in utero and, in a subset of patients, may progress to serious late manifestations. Numerous studies have demonstrated that syphilis, in the early stages, increases the risk of acquisition and transmission of human immunodeficiency virus. Despite the availability of inexpensive and effective penicillin therapy, syphilis is epidemic in the United States and in many parts of the developing world. Therefore, prevention of syphilis infection through development of an effective vaccine is an important goal. The most rational strategy for developing a vaccine for syphilis would be to define and exploit the protective mechanisms of immunity demonstrated in the resolution of lesions and maintenance of the asymptomatic latent stage. While antibodies develop early in syphilis infection, the are inadequate alone to control infection, and cellular immunity is thought to be crucial. Studies conducted in the rabbit model of syphilis have led us to hypothesize that the mechanism of clearance of early lesions is mediated by macrophages activated by cytokine products of T lymphocytes. These studies have been limited, however, by the lack of immunological reagents for the rabbit. Therefore, it is essential to address key questions concerning the immune response to syphilis in humans, where reagents are available for identifying T cell subsets, T cell receptor molecules, and cytokines. In the proposed studies, we will define, at the cellular and molecular level, the mechanisms of clearance of Treponema pallidum from primary and secondary syphilis lesions, including phenotypes of infiltrating cells and local production of cytokines. Cloned T cells, derived directly from lesions, will be used to identify the T cell epitopes of relevant treponemal antigens and to examine specific cytokine production by reactive T lymphocytes. The function of these cytokines to activate macrophages for ingestion and killing of T. pallidum will be measured. These studies will define the protective immune mechanisms in syphilis infections and the antigenic epitopes inducing those responses; this information will be directly relevant to the rational development of a candidate syphilis vaccine.